The effects of hyperbilirubinemia in premature infants, or in infants with hemolytic disease, may be deleterious and different than in well, term infants. Therefore, it is important to distinguish between those infants who are at low risk and those who are at high risk to develop potentially dangerous jaundice due to increased bilirubin production or to poor elimination. In our first specific aim, we propose to examine well, term neonates using noninvasive measurements of carbon monoxide in breath (an index of bilirubin production) and of transcutaneous bilirubin (an index of bilirubin accumulation). The study design and statistical methods for this aim have been reevaluated and explained in detail by a professional statistician. From these data, we will formulate criteria to identify neonates who are either at low risk or at high risk for developing potentially dangerous jaundice. The application of the low risk criteria to neonates will permit a pediatrician to reduce infant hospitalization after birth. In our second specific aim, we propose to continue our assessment and characterization of selected metalloporphyrin heme oxygenase (HO) inhibitors of bilirubin production, with respect to their efficacy and safety in neonatal rat and nonhuman primate models of increased bilirubin production. Metalloporphyrins will be selected according to the following criteria through an in-depth staged screening program: i) potent heme oxygenase (HO) inhibition; ii) negligible photoreactivity; iii) minimal catabolism; and iv) lack of short- and long-term metabolic side effects. A reduced, three-year budget is proposed. No funding is requested for our third specific aim which is contingent upon FDA approval and our ability to identify the safest effective metalloporphyrin, as well as an appropriate group of high risk neonates selected from among those with severe hyperbilirubinemia due to isoimmune hemolytic disease. In this aim, we propose to design and conduct a double-blind, randomized, placebo-controlled clinical trial of the selected HO inhibitor of bilirubin production, in neonates who are at high risk for developing potentially dangerous jaundice, and who have a greater than 80% probability of receiving an exchange transfusion. Through the accomplishment of these goals, we believe we can facilitate, for low risk neonates, an early discharge from the hospital and outpatient management of transitional hyperbilirubinemia. In addition, through our laboratory studies and contingent clinical trial, we believe that we can develop a safe and efficacious chemopreventive strategy for high risk neonates as an alternative to risk-laden exchange transfusions.